Positron Emission Tomography (PET) has become one of the most prominent functional imaging modalities in diagnostic medicine, with very high sensitivity (fmol), high resolution (4-10 mm) and tissue accretion that can be adequately quantitated. Although [18F]2-deoxy-2-fluoro-D-glucose (18FDG) is the most widely used PET imaging agent in oncology, there is a keen interest in developing other labeled compounds for functional imaging to complement and augment anatomic imaging methods. Thus, there is a need to have facile methods of conjugating positron emitting radionuclides to various molecules of biological and medical interest.
WO 2011/095150 A1 (corresponding to DE 10210007097 A1) discloses conjugates of 18F carriers having bioactive organic compounds and their methods of preparation. The carrier comprises a metallocene complex fixed on a solid support, preferably via a phosphine linker. The preparation of the 18F-labeled targeting molecule requires a multi-step process. First, the metallocene complex is fixed onto the solid support, then 18F is added to replace the original metal protective groups, typically Cl, with 18F. Then the Cl− ions and the excess of 18F are eluted from the solid support. In a next step a targeting molecule is added to the 18F-labeled metallocene complex fixed on the solid support to bind the targeting molecule to the 18F-labeled metallocene complex. Finally the labeled targeting molecule is eluted from the solid support, and, after the elution, a purified 18F-labeled targeting molecule is collected. This latter is suitable for in vivo imaging.
DE 102011109187 A1 discloses conjugation agents useful e.g. for bioassay and in medical diagnosis. The agents comprise a protected Staudinger component that is convertible into unprotected Staudinger component before conjugation reaction, and is linked with carrier by spacer group.
Both the agents of DE 102011109187 A1 and the conjugates of DE 10210007097 A1 (discussed above) disclose bis-cyclopentadienyl titanocene structures bearing on one or both of the cyclopentadienyl rings substituents consisting of only aliphatic chains with terminal functional groups.
Qian, Yanlong, et al., Polyhedron (1993), 12(8), 967-70; Causey, Patrick W. et al, Organometallics (2004), 23, 4486-4494; EP 953580; and EP 955306 disclose bis-cyclopentadienyl titanocene structures bearing on one or both of the cyclopentadienyl rings substituents consisting of aliphatic chains —(CH2)n— with terminal functional groups such as —OH or NH3Cl.
DE 102006054690 A1 discloses substituted metallocene structures including a bis-cyclopentadienyl titanocene having a carboxylate terminal group linked to one of the cyclopentadienyl group via a substituted alkylene chain (compound VIII).
Thus a need exists for a rapid and simple method of 18F labeling of targeting moieties, such as proteins or peptides, which results in targeting constructs of suitable specific activity and in vivo stability for detection and/or imaging, while avoiding use of solid support, minimizing the requirements for specialized equipment or highly trained personnel and reducing operator exposure to high levels of radiation. Also, a need exists for compounds suitable to be linked to a protein, peptide or other targeting molecule to form precursors of 18F labeled targeting molecules. A further need exists for prepackaged kits that could provide compositions required for performing such novel methods.